Pyridin-2-one derivatives of formula (I) useful as EP3 receptor antagonists

Abstract

The present invention is directed to pyridin-2-one derivatives, pharmaceutical compositions containing them and their use as antagonists of the EP3 receptor, for the treatment of for example, impaired oral glucose tolerance, elevated fasting glucose, Type II Diabetes Mellitus, Syndrome X (also known as Metabolic Syndrome) and related disorders and complications thereof.

What is claimed: 
     
       1. A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and 2,3-dihydro-benzo[b][1,4]dioxin-6-yl;
 wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or 2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is optionally substituted on the phenyl portion of the 
 
       
         
           
           
               
               
           
         
       
       bicycle with one to two substituents independently selected from the group consisting of halogen, oxo, cyano, C 1-3 alkyl, fluorinated C 1-2 alkyl, C 1-3 alkoxy, fluorinated C 1-2 alkoxy and C 3-6 cycloalkyl;
 and wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or 2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is further optionally substituted on the 
 
       
         
           
           
               
               
           
         
       
       portion of the 
       
         
           
           
               
               
           
         
       
       bicycle with one to two substituents independently selected from the group consisting of halogen, oxo, cyano, C 1-3 alkyl, fluorinated C 1-2 alkyl, C 1-3 alkoxy, fluorinated C 1-2 alkoxy and C 3-6 cycloalkyl;
 R 1  is selected from the group consisting of hydrogen, halogen and C 1-4 alkyl; 
 R 2  is selected from the group consisting of hydrogen, halogen and C 1-4  alkyl; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of —CR A R B —, —CR A R B —CH 2 —, —CH 2 —CHR C —, —CR A R B —CR C ═, —C(R A )═, —CR A R B —N(R D )—, —CR A R B —CH 2 —N(R D )—, —CR A R B —C(O)—N(R D )—, —CR A R B —CH 2 —C(O)—N(R D )—, —CR A R B —C(O)—N(R D )—SO 2 —, —CR A R B —CH 2 —C(O)—N(R D )—SO 2 —, —CR A R B —N(R D )—SO 2 —, —CR A R B —CH 2 —N(R D )—SO 2 , and —CR A R B —CH 2 —SO 2 —; wherein the X group is incorporated in the orientation as listed;
 wherein R A  and R B  are each independently selected from the group consisting of hydrogen, fluoro, C 1-6 alkyl, fluorinated C 1-2 alkyl, C 3-6 cycloalkyl, phenyl, benzyl, phenyl-ethyl- and —C(O)—OC 2 alkyl; provided that when one of R A  or R B  is C 3-6 cycloalkyl, phenyl, benzyl, phenyl-ethyl- or —C(O)O-C 2 alkyl, then the other of R A  or R B  is hydrogen; 
 alternatively, when X is selected from the group consisting of —CR A R B —, —CR A R B —CH 2 — and —CR A R B —CR C ═, R A  and R B  may be taken together with the carbon atom to which they are bound to form C 3-6 cycloalkyl; 
 R C  is selected from the group consisting of hydrogen and C 1-3 alkyl; 
 R D  is selected from the group consisting of hydrogen and C 1-3 alkyl; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of C 5-6 cycloalkyl, C 5-6 cycloalkenyl, phenyl, four to six membered monocyclic heterocyclyl and nine to ten membered bicyclic heterocyclyl;
 wherein the phenyl, four to six membered monocyclic heterocyclyl or nine to ten membered bicyclic heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, C 1-4 alkyl, fluorinated C 1-2 alkyl, —NR D R E , cyano, imino, cyanoimino, —S—(C 1-4 alkyl), —SO—(C 1-4 alkyl), —SO 2 —(C 1-4 alkyl), —C(O)OH, —C(O)O—(C 1-3 alkyl) and —C(O)—NR D R E ; 
 wherein R D  and R E  are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; 
 or a tautomer or a pharmaceutically acceptable salt thereof. 
 
     
     
       2. A compound as in  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, and 2,3-dihydro-benzo[b][1,4]dioxin-6-yl;
 wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or 2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is optionally substituted on the phenyl portion of the 
 
       
         
           
           
               
               
           
         
       
       bicycle with one to two substituents independently selected from the group consisting of halogen, oxo, cyano, C 1-3 alkyl, fluorinated C 1-2 alkyl, C 1-3 alkoxy, fluorinated C 1-2 alkoxy and C 3-6 cycloalkyl;
 and wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl or 2,3-dihydro-benzo[b]1,4]dioxin-6-yl is further optionally substituted on the 
 
       
         
           
           
               
               
           
         
       
       portion of the 
       
         
           
           
               
               
           
         
       
       bicycle with one to two substituents independently selected from the group consisting of halogen, oxo, cyano, C 1-3 alkyl, fluorinated C 1-2 alkyl, C 1-3 alkoxy, fluorinated C 1-2 alkoxy and C 3-6 cycloalkyl;
 R 1  is selected from the group consisting of hydrogen, halogen and C 1-2 alkyl; 
 R 2  is selected from the group consisting of hydrogen, halogen and C 1-2 alkyl; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of —CR A R B —, —CR A R B —CH 2 —, —CH 2 —CHR C —, —CR A R B —CR C ═, —C(R A )═, —CR A R B —N(R D )—, —CR A R B —CH 2 —N(R D )—, —CR A R B —C(O)—N(R D )—, —CR A R B —CH 2 —C(O)—N(R D )—, —CR A R B —C(O)—N(R D )—SO 2 —, —CR A R B —CH 2 —C(O)—N(R D )—SO 2 —, —CR A R B —N(R D )—SO 2 —, —CR A R B —CH 2 —N(R D )—SO 2 ; and —CR A R B —CH 2 —SO 2 —; wherein the X group is incorporated in the orientation as listed;
 wherein R A  and R B  are each independently selected from the group consisting of hydrogen, fluoro, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, benzyl and —C(O)—OC 1-2 alkyl; provided that when one of R A  or R B  is C 3-6 cycloalkyl, phenyl, benzyl, or —C(O)O—C 1-2 alkyl, then the other of R A  or R B  is hydrogen; 
 alternatively, when X is selected from the group consisting of —CR A R B —CH 2 — and —CR A R B —CR C ═, R A  and R B  may be taken together with the carbon atom to which they are bound to form C 3-6 cycloalkyl; 
 R C  is selected from the group consisting of hydrogen and C 1-3 alkyl; 
 R D  is selected from the group consisting of hydrogen and C 1-3 alkyl; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of C 5-6 cycloalkyl, C 5-6 cycloalkenyl, phenyl, four to six membered monocyclic heterocyclyl and nine to ten membered bicyclic heterocyclyl;
 wherein the phenyl, four to six membered monocyclic heterocyclyl or nine to ten membered bicyclic heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, oxo, C 1-4 alkyl, fluorinated C 1-2 alkyl, —NR D R E , cyano, imino, cyanoimino, —SO 2 —(C 1-2 alkyl), —C(O)OH, —C(O)O—(C 1-3 alkyl) and —C(O)—NR D R E ; 
 wherein R D  and R E  are each independently selected from the group consisting of hydrogen and C 1-2 alkyl; 
 or a tautomer or a pharmaceutically acceptable salt thereof. 
 
     
     
       3. A compound as in  claim 2 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl and 2,3-dihydro-benzo[b][1,4]dioxin-6-yl;
 wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl or 2,3-dihydro-benzo[b][1,4]dioxin-6-yl; is optionally substituted on the phenyl portion of the 
 
       
         
           
           
               
               
           
         
       
       bicycle with one to two substituents independently selected from the group consisting of halogen, oxo, cyano, C 1-3 alkyl, fluorinated C 1-2 alkyl and C 3-6 cycloalkyl;
 and wherein the naphth-2-yl, indol-5-yl, indazol-5-yl, indazol-6-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzoisothiazol-6-yl, chroman-7-yl, chromen-7-yl, benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, or 2,3-dihydro-benzo[b][1,4]dioxin-6-yl is further optionally substituted on the 
 
       
         
           
           
               
               
           
         
       
       portion of the 
       
         
           
           
               
               
           
         
       
       bicycle with one to two substituents independently selected from the group consisting of halogen, oxo, cyano, C 1-3 alkyl, fluorinated C 1-2 alkyl and C 3-6 cycloalkyl;
 R 1  is selected from the group consisting of hydrogen, halogen and C 1-2 alkyl; 
 R 2  is hydrogen; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of —CR A R B —, —CR A R B —CH 2 —, —CH 2 —CHR C —, —CR A R B —CR C ═, —C(R A )═, —CR A R B —N(R D )—, —CR A R B —C(O)—N(R D )—, —CR A R B —CH 2 —C(O)—N(R D )—, —CR A R B —C(O)—N(R D )—SO 2 —, —CR A R B —CH 2 —C(O)—N(R D )—SO 2 —, —CR A R B —N(R D )—SO 2 — and —CR A R B —CH 2 —SO 2 —; wherein the X group is incorporated in the orientation as listed;
 wherein R A  and R B  are each independently selected from the group consisting of hydrogen, fluoro, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, benzyl and —C(O)O—(C 1-2 alkyl); provided that when one of R A  or R B  is C 3-6 cycloalkyl, phenyl, benzyl or —C(O)O—C 1-2 alkyl, then the other of R A  or R B  is hydrogen; 
 alternatively, when X is selected from the group consisting of —CR A R B —CH 2 — and —CR A R B —CR C ═, R A  and R B  may be taken together with the carbon atom to which they are bound to form C 3-5 cycloalkyl; 
 R C  is selected from the group consisting of hydrogen and C 1-3 alkyl; 
 R D  is hydrogen; 
 
       
         
           
           
               
               
           
         
         is selected from the group consisting of C 5-6 cycloalkyl, C 5-6 cycloalkenyl, phenyl, four to six membered monocyclic heterocyclyl and nine to ten membered bicyclic heterocyclyl; 
         wherein the phenyl, four to six membered monocyclic heterocyclyl or nine to ten membered bicyclic heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, oxo, C 1-4 alkyl, trifluoromethyl, —NR D R E , imino, cyanoimino and —SO 2 —(C 1-2 alkyl); 
         wherein R D  and R E  are each independently selected from the group consisting of hydrogen and C 1-2 alkyl; 
         or a tautomer or a pharmaceutically acceptable salt thereof. 
       
     
     
       4. A compound as in  claim 3 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of naphth-2-yl, 8-fluoro-naphth-2-yl, 5,7-difluoro-naphth-2-yl, 6,8-difluoro-naphth-2-yl, 8-ethyl-naphth-2-yl, 8-isopropyl-naphth-2-yl, 8-trifluoromethyl-naphth-2-yl, 8-cyano-naphth-2-yl, 2,2-dimethyl-chroman-7-yl, 2,2-dimethyl-chromen-7-yl, 1-methyl-indol-5-yl, 2-ethyl-indazol-6-yl, 1-ethyl-4-chloro-indazol-6-yl, 1-ethyl-4-fluoro-indazol-6-yl, 2-ethyl-4-fluoro-indazol-5-yl, 2-ethyl-4-methyl-indazol-6-yl, 1-ethyl-3-methyl-indazol-6-yl, 1-ethyl-4-methyl-indazol-6-yl, 1-ethyl-5-methyl-indazol-6-yl, 1-ethyl-5-fluoro-indazol-6-yl, 2-ethyl-4-methyl-indazol-6-yl, 1-isopropyl-4-fluoro-indazol-6-yl, 1-cyclopentyl-4-fluoro-indazol-6-yl, 1-methyl-7-chloro-benzimidazol-5-yl, 1-ethyl-7-fluoro-benzimidazol-6-yl, benzoisothiazol-6-yl, 4-methyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl, 4-ethyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl, 4-ethyl-8-fluoro-3,4-dihydro-benzo[b][1,4]oxazin-6-yl, 4-ethyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl-3-one, 2,3-dihydro-benzo[b][1,4]dioxin-6-yl and 2,2-difluoro-benzo[d][1,3]dioxol-5-yl;
 R 1  is selected from the group consisting of hydrogen, fluoro, chloro, bromo and methyl; 
 R 2  is hydrogen; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of —CH 2 —, —C(ethyl) 2 -, —CH(isopropyl)-, -(syn)-CH(isopropyl)-, -(anti)-CH(isopropyl)-, -(syn)-CH(S-isopropyl)-CH 2 —, -(anti)-CH(S-isopropyl)-CH 2 —, —CH(C(O)O-ethyl)-, —C(methyl) 2 -CH 2 —, —C(ethyl) 2 -CH 2 —, —CH(isopropyl)-CH 2 —, —CH 2 —CH(isopropyl)-, -(syn)-CH(isopropyl)-CH 2 —, -(anti)-CH(isopropyl)-CH 2 —, —C(methyl) 2 -CH═, —C(methyl) 2 -(Z)—CH═, —C(methyl) 2 -(E)-CH═, —C(ethyl) 2 -CH═, —C(ethyl) 2 -(E)-CH═, —C(ethyl) 2 -(Z)—CH═, —CH(isopropyl)-CH═, —CH(isopropyl)-(E)-CH═, —CH(isopropyl)-(Z)—CH═, —CH(R*-isopropyl)-(Z)—CH═, —CH(S*-isopropyl)-(Z)—CH═, —CH(isopropyl)-(E)-C(methyl)=, —CH(isopropyl)-(Z)—C(methyl)=, —CH(t-butyl)-(E)-CH═, —CH(n-pent-3-yl)-(E)-CH═, —CH(cyclopropyl)-(Z)—CH═, —CH(cyclopentyl)-(Z)—CH═, —CH(cyclopentyl)-(E)-CH═, —CH(cyclohexyl)-(Z)—CH═, —CH(cyclohexyl)-(E)-CH═, —CH(phenyl)-(Z)—CH═, —CH(benzyl)-(E)-CH═, —CH 2 -(E)-C(isopropyl)=, —CH(C(O)O-ethyl)=, —(Z)—C(isopropyl)=, -(E)-C(isopropyl)=, -cyclopropyl-1,1-yl-(E)-CH═, -cyclopent-1,1-yl-CH 2 —, -cyclopent-1,1-yl-(E)-CH═, —CH(isopropyl)-CH 2 —SO 2 —, —CH(isopropyl)-NH—, —CH(isopropyl)-C(O)—NH—, —CH(isopropyl)-CH 2 —C(O)—NH—, —CH(isopropyl)-C(O)—NH—SO 2 —, —CF(isopropyl)-C(O)—NH—SO 2 —, —CH(isopropyl)-CH 2 —C(O)—NH—SO 2 , and —CH(isopropyl)-NH—SO 2 —;
 wherein the X group is incorporated in the orientation as listed; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of cyclohexyl, cyclohex-1-en-1-yl, 3,5-difluoro-phenyl, azetidin-3-yl, 1-methyl-azetidin-3-yl, pyrrolidin-3-yl, pyrrolidin-3-yl-2-one, R-pyrrolidin-3-yl-2-one, S-pyrrolidin-3-yl-2-one, 3-methyl-pyrrolidin-3-yl-2-one, piperidin-1-yl-2-one, piperidin-3-yl-2-one, 1-(methylsulfonyl)-piperidin-4-yl, 4-(methylsulfonyl)-piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl-1,1-dioxide, tetrahydropyran-4-yl, tetrahydro-thiopyran-4-yl, tetrahydro-thiopyran-4-yl-1,1-dioxide, 1,2-thiazinan-2-yl-1,1-dioxide, imidazol-2-yl, 5-methyl-imidazol-2-yl, 4,5-dimethyl-imidazol-2-yl, 2-amino-imidazol-1-yl, imidazolidin-1-yl-2-one, imidazolidin-5-yl-2,4-dione, 1-methyl-imidazolidin-5-yl-2,4-dione, 2-(cyanoimino)-imidazolidin-1-yl, 5-isopropyl-imidazolidin-5-yl-2,4-dione, 1-methyl-benzimidazol-5-yl, 1,5-dihydro-pyrrol-3-yl-2-one, 4,5-dichloro-thien-2-yl, pyridin-3-yl, oxazol-2-yl, oxazolidin-5-yl-2,4-dione, 5-isopropyl-oxazolidin-5-yl-2,4-dione, thiazolidin-5-yl-2,4-dione, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl-5-one, 1,3,4-oxadiazol-2-yl, 5-methyl-i 1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 5-isopropyl-1,3,4-oxadiazol-2-yl, 5-trifluoromethyl-1,3,4-oxadiazol-2-yl, 5-amino-1,3,4-oxadiazol-2-yl, 5-(dimethylamino)-1,3,4-oxadiazol-2-yl, thiazol-2-yl, 2-amino-thiazol-5-yl, 2-imino-thiazol-3-yl, 5-amino-1,3,4-thiadiazol-2-yl, 5-(dimethylamino)-1,3,4-thiadiazol-2-yl, 1,3,4-triazol-2-yl, 1-methyl-1,3,4-triazol-5-yl, 5-methyl-i 1,3,4-triazol-2-yl, 2-amino-1,3,4-triazol-1-yl, 1-methyl-1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 3-amino-1,2,4-triazol-1-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl and 1,2,3,5-tetrazol-4-yl;
 or a tautomer or a pharmaceutically acceptable salt thereof. 
 
     
     
       5. A compound as in  claim 4 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of naphth-2-yl, 8-fluoro-naphth-2-yl, 5,7-difluoro-naphth-2-yl, 6,8-difluoro-naphth-2-yl, 8-ethyl-naphth-2-yl, 8-isopropyl-naphth-2-yl, 8-trifluoromethyl-naphth-2-yl, 8-cyano-naphth-2-yl, 1-methyl-indol-5-yl, 1-ethyl-4-chloro-indazol-6-yl, 1-ethyl-4-fluoro-indazol-6-yl, 1-ethyl-5-fluoro-indazol-6-yl, 1-ethyl-4-methyl-indazol-6-yl, 2-ethyl-4-methyl-indazol-6-yl, 1-isopropyl-4-fluoro-indazol-6-yl, 1-cyclopentyl-4-fluoro-indazol-6-yl, 1-methyl-7-chloro-benzimidazol-5-yl, 4-methyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl, 4-ethyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl, 4-ethyl-8-fluoro-3,4-dihydro-benzo[b][1,4]oxazin-6-yl, 4-ethyl-3,4-dihydro-benzo[b][1,4]oxazin-6-yl-3-one and 2,3-dihydro-benzo[b][1,4]dioxin-6-yl;
 R 1  is selected from the group consisting of hydrogen, fluoro and methyl; 
 R 2  is hydrogen; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of —CH 2 —, —C(ethyl) 2 -, —CH(isopropyl)-, -(syn)-CH(isopropyl)-, -(anti)-CH(isopropyl)-, —CH(C(O)O-ethyl)-, —C(methyl) 2 -CH 2 —, —C(ethyl) 2 -CH 2 —, —CH(isopropyl)-CH 2 —, -(syn)-CH(isopropyl)-CH 2 —, -(anti)-CH(isopropyl)-CH 2 —, -(syn)-CH(S-isopropyl)-CH 2 —, -(anti)-CH(S-isopropyl)-CH 2 —, —CH 2 —CH(isopropyl)-, —C(methyl) 2 -(Z)—CH═, —C(ethyl) 2 -(E)-CH═, —C(ethyl) 2 -(Z)—CH═, —CH(isopropyl)-CH═, —CH(isopropyl)-(E)-CH═, —CH(isopropyl)-(Z)—CH═, —CH(R*-isopropyl)-(Z)—CH═, —CH(S*-isopropyl)-(Z)—CH═, —CH(isopropyl)-(E)-C(methyl)=, —CH(isopropyl)-(Z)—C(methyl)=, —CH(n-pent-3-yl)-(E)-CH═, —CH(cyclopropyl)-(Z)—CH═, —CH(cyclopentyl)-(E)-CH═, —CH(cyclopentyl)-(Z)—CH═, —CH(cyclohexyl)-(E)-CH═, —CH(cyclohexyl)-(Z)—CH═, —CH(phenyl)-(Z)—CH═, —CH(benzyl)-(E)-CH═, —CH 2 -(E)-C(isopropyl)=, —CH(C(O)O-ethyl)=, —(Z)—C(isopropyl)=, -(E)-C(isopropyl)=, -cyclopropyl-1,1-yl-(E)-CH═, -cyclopent-1,1,-yl-CH 2 —, -cyclopent-1,1,-yl-(E)-CH═, —CH(isopropyl)-CH 2 —SO 2 —, —CH(isopropyl)-NH—, —CH(isopropyl)-C(O)—NH—, —CH(isopropyl)-CH 2 —C(O)—NH—, —CH(isopropyl)-C(O)—NH—SO 2 —, —CF(isopropyl)-C(O)—NH—SO 2 —, —CH(isopropyl)-CH 2 —C(O)—NH—SO 2 , and —CH(isopropyl)-NH—SO 2 —; wherein the X group is incorporated in the orientation as listed; 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of cyclohexyl, cyclohex-1-en-1-yl, 3,5-difluoro-phenyl, azetidin-3-yl, 1-methyl-azetidin-3-yl, pyrrolidin-3-yl, pyrrolidin-3-yl-2-one, R-pyrrolidin-3-yl-2-one, S-pyrrolidin-3-yl-2-one, 3-methyl-pyrrolidin-3-yl-2-one, piperidin-1-yl-2-one, piperidin-3-yl-2-one, 1-(methylsulfonyl)-piperidin-4-yl, 4-(methylsulfonyl)-piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl-1,1-dioxide, tetrahydropyran-4-yl, tetrahydro-thiopyran-4-yl, tetrahydro-thiopyran-4-yl-1,1-dioxide, 1,2-thiazinan-2-yl-1,1-dioxide, imidazol-2-yl, 5-methyl-imidazol-2-yl, 4,5-dimethyl-imidazol-2-yl, 2-amino-imidazol-1-yl, imidazolidin-1-yl-2-one, imidazolidin-5-yl-2,4-dione, 1-methyl-imidazolidin-5-yl-2,4-dione, 2-(cyanoimino)-imidazolidin-1-yl, 5-isopropyl-imidazolidin-5-yl-2,4-dione, 1-methyl-benzimidazol-5-yl, 4,5-dichloro-thien-2-yl, pyridin-3-yl, oxazol-2-yl, oxazolidin-5-yl-2,4-dione, 5-isopropyl-oxazolidin-5-yl-2,4-dione, thiazolidin-5-yl-2,4-dione, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl-5-one, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 5-isopropyl-1,3,4-oxadiazol-2-yl, 5-trifluoromethyl-1,3,4-oxadiazol-2-yl, 5-(dimethylamino)-1,3,4-oxadiazol-2-yl, thiazol-2-yl, 2-amino-thiazol-5-yl, 2-imino-thiazol-3-yl, 5-amino-1,3,4-thiadiazol-2-yl, 5-(dimethylamino)-1,3,4-thiadiazol-2-yl, 1,3,4-triazol-2-yl, 1-methyl-1,3,4-triazol-5-yl, 5-methyl-i 1,3,4-triazol-2-yl, 2-amino-1,3,4-triazol-1-yl, 1-methyl-1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 3-amino-1,2,4-triazol-1-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl and 1,2,3,5-tetrazol-4-yl;
 or a tautomer or a pharmaceutically acceptable salt thereof. 
 
     
     
       6. A compound as in  claim 4 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of naphth-2-yl, 8-fluoro-naphth-2-yl, 5,7-difluoro-naphth-2-yl, 8-ethyl-naphth-2-yl, 1-methyl-indol-5-yl, 1-ethyl-4-chloro-indazol-6-yl, 1-ethyl-4-fluoro-indazol-6-yl, 1-isopropyl-4-fluoro-indazol-6-yl, 4-ethyl-8-fluoro-3,4-dihydro-benzo[b][1,4]oxazin-6-yl and 2,3-dihydro-benzo[b][1,4]dioxin-6-yl;
 R 1  is selected from the group consisting of hydrogen, fluoro and methyl; 
 R 2  is hydrogen; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of —C(ethyl) 2 -, —CH(isopropyl)-, -(anti)-CH(isopropyl)-, —C(methyl) 2 -CH 2 —, —C(ethyl) 2 -CH 2 —, —CH(isopropyl)-CH 2 —, -(syn)-CH(isopropyl)-CH 2 —, -(anti)-CH(isopropyl)-CH 2 —, -(syn)-CH(S-isopropyl)-CH 2 —, -(anti)-CH(S-isopropyl)-CH 2 —, —CH 2 —CH(isopropyl)-, —C(methyl) 2 -(Z)—CH═, —C(ethyl) 2 -(E)-CH═, —C(ethyl) 2 -(Z)—CH═, —CH(isopropyl)-(E)-CH═, —CH(isopropyl)-(Z)—CH═, —CH(R*-isopropyl)-(Z)—CH═, —CH(S*-isopropyl)-(Z)—CH═, —CH(isopropyl)-(E)-C(methyl)=, —CH(isopropyl)-(Z)—C(methyl)=, —CH(n-pent-3-yl)-(E)-CH═, —CH(cyclopropyl)-(Z)—CH═, —CH(cyclopentyl)-(E)-CH═, —CH(cyclopentyl)-(Z)—CH═, —CH(cyclohexyl)-(E)-CH═, —CH(cyclohexyl)-(Z)—CH═, —CH(phenyl)-(Z)—CH═, —CH(benzyl)-(E)-CH═, —CH(C(O)O-ethyl)=, —(Z)—C(isopropyl)=, -(E)-C(isopropyl)=, -cyclopropyl-1,1-yl-(E)-CH═, -cyclopent-1,1,-yl-CH 2 —, -cyclopent-1,1,-yl-(E)-CH═, —CH(isopropyl)-CH 2 —SO 2 —, —CH(isopropyl)-NH—, —CH(isopropyl)-C(O)—NH—, —CH(isopropyl)-CH 2 —C(O)—NH—, and —CH(isopropyl)-NH—SO 2 —; wherein the X group is incorporated in the orientation as listed; 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of cyclohexyl, azetidin-3-yl, 1-methyl-azetidin-3-yl, pyrrolidin-3-yl, pyrrolidin-3-yl-2-one, R-pyrrolidin-3-yl-2-one, S-pyrrolidin-3-yl-2-one, 3-methyl-pyrrolidin-3-yl-2-one, piperidin-1-yl-2-one, piperidin-3-yl-2-one, 1-(methylsulfonyl)-piperidin-4-yl, 4-(methylsulfonyl)-piperazin-1l-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl-1,1-dioxide, tetrahydropyran-4-yl, tetrahydro-thiopyran-4-yl, tetrahydro-thiopyran-4-yl-1,1-dioxide, 1,2-thiazinan-2-yl-1,1-dioxide, imidazol-2-yl, 5-methyl-imidazol-2-yl, 4,5-dimethyl-imidazol-2-yl, 2-amino-imidazol-1l-yl, imidazolidin-1l-yl-2-one, imidazolidin-5-yl-2,4-dione, 1-methyl-imidazolidin-5-yl-2,4-dione, 2-(cyanoimino)-imidazolidin-1l-yl, 1-methyl-benzimidazol-5-yl, pyridin-3-yl, oxazol-2-yl, oxazolidin-5-yl-2,4-dione, thiazolidin-5-yl-2,4-dione, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl-5-one, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 5-isopropyl-1,3,4-oxadiazol-2-yl, 5-(dimethylamino)-1,3,4-oxadiazol-2-yl, thiazol-2-yl, 2-amino-thiazol-5-yl, 2-imino-thiazol-3-yl, 5-amino-1,3,4-thiadiazol-2-yl, 5-(dimethylamino)-1,3,4-thiadiazol-2-yl, 1,3,4-triazol-2-yl, 5-methyl-i 1,3,4-triazol-2-yl, 2-amino-1,3,4-triazol-1-yl, 1-methyl-1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 3-amino-1,2,4-triazol-1-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl and 1,2,3,5-tetrazol-4-yl;
 or a tautomer or a pharmaceutically acceptable salt thereof. 
 
     
     
       7. A compound as in  claim 4 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 8-fluoro-naphth-2-yl, 8-ethyl-naphth-2-yl, 1-ethyl-4-chloro-indazol-6-yl, 1-ethyl-4-fluoro-indazol-6-yl and 4-ethyl-8-fluoro-3,4-dihydro-benzo[b][1,4]oxazin-6-yl;
 R 1  is selected from the group consisting of hydrogen, fluoro and methyl; 
 R 2  is hydrogen; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of —C(ethyl) 2 -, —CH(isopropyl), —C(ethyl) 2 -CH 2 —, —CH(isopropyl)-CH 2 —, -(syn)-CH(isopropyl)-CH 2 —, -(anti)-CH(isopropyl)-CH 2 —, -(syn)-CH(S-isopropyl)-CH 2 —, -(anti)-CH(S-isopropyl)-CH 2 —, —CH 2 —CH(isopropyl)-, —C(ethyl) 2 -(E)-CH═, —C(ethyl) 2 -(Z)—CH═, —CH(isopropyl)-(E)-CH═, —CH(isopropyl)-(Z)—CH═, —CH(R*-isopropyl)-(Z)—CH═, —CH(S*-isopropyl)-(Z)—CH═, —CH(isopropyl)-(E)-C(methyl)=, —CH(isopropyl)-(Z)—C(methyl)=, —CH(cyclopropyl)-(Z)—CH═, —CH(cyclopentyl)-(E)-CH═, —CH(cyclopentyl)-(Z)—CH═, —CH(cyclohexyl)-(Z)—CH═, —CH(phenyl)-(Z)—CH═, —(Z)—C(isopropyl)=, -(E)-C(isopropyl)=, —CH(isopropyl)-NH— and —CH(isopropyl)-C(O)—NH—; wherein the X group is incorporated in the orientation as listed; 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl, pyrrolidin-3-yl-2-one, R-pyrrolidin-3-yl-2-one, S-pyrrolidin-3-yl-2-one, 3-methyl-pyrrolidin-3-yl-2-one, piperidin-1-yl-2-one, piperidin-3-yl-2-one, 1-(methylsulfonyl)-piperidin-4-yl, 4-(methylsulfonyl)-piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl-1,1-dioxide, tetrahydropyran-4-yl, tetrahydro-thiopyran-4-yl, tetrahydro-thiopyran-4-yl-1,1-dioxide, 1,2-thiazinan-2-yl-1,1-dioxide, imidazol-2-yl, 5-methyl-imidazol-2-yl, 4,5-dimethyl-imidazol-2-yl, 2-amino-imidazol-1-yl, imidazolidin-1-yl-2-one, 1-methyl-imidazolidin-5-yl-2,4-dione, 2-(cyanoimino)-imidazolidin-1-yl, 1-methyl-benzimidazol-5-yl, pyridin-3-yl, oxazol-2-yl, oxazolidin-5-yl-2,4-dione, thiazolidin-5-yl-2,4-dione, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl-5-one, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 5-isopropyl-1,3,4-oxadiazol-2-yl, 5-(dimethylamino)-1,3,4-oxadiazol-2-yl, thiazol-2-yl, 2-amino-thiazol-5-yl, 2-imino-thiazol-3-yl, 5-amino-1,3,4-thiadiazol-2-yl, 5-(dimethylamino)-1,3,4-thiadiazol-2-yl, 1,3,4-triazol-2-yl, 2-amino-1,3,4-triazol-1-yl, 1,2,4-triazol-5-yl and 1,2,3,4-tetrazol-5-yl;
 or a tautomer or a pharmaceutically acceptable salt thereof. 
 
     
     
       8. A compound as in  claim 4 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 8-fluoro-naphth-2-yl, 1-ethyl-4-chloro-indazol-6-yl, 1-ethyl-4-fluoro-indazol-6-yl and 4-ethyl-8-fluoro-3,4-dihydro-benzo[b][1,4]oxazin-6-yl;
 R 1  is hydrogen; 
 R 2  is hydrogen; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of —C(ethyl) 2 -, —CH(isopropyl)-, —C(ethyl) 2 -CH 2 —, —CH(isopropyl)-CH 2 —, -(syn)-CH(isopropyl)-CH 2 —, -(anti)-CH(isopropyl)-CH 2 —, -(syn)-CH(S-isopropyl)-CH 2 —, -(anti)-CH(S-isopropyl)-CH 2 —, —C(ethyl) 2 -(E)-CH═, —C(ethyl) 2 -(Z)—CH═, —CH(isopropyl)-(E)-CH═, —CH(isopropyl)-(Z)—CH═, —CH(S*-isopropyl)-(Z)—CH═, —CH(isopropyl)-(E)-C(methyl)=, —CH(cyclopentyl)-(Z)—CH═, —CH(cyclohexyl)-(Z)═CH═, —CH(isopropyl)-NH- and —CH(isopropyl)-C(O)—NH—; wherein the X group is incorporated in the orientation as listed; 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of pyrrolidin-3-yl-2-one, R-pyrrolidin-3-yl-2-one, S-pyrrolidin-3-yl-2-one, 3-methyl-pyrrolidin-3-yl-2-one, piperidin-1-yl-2-one, piperidin-3-yl-2-one, 1-(methylsulfonyl)-piperidin-4-yl, morpholin-4-yl, thiomorpholin-4-yl-1,1-dioxide, tetrahydropyran-4-yl, tetrahydro-thiopyran-4-yl, tetrahydro-thiopyran-4-yl-1,1-dioxide, imidazol-2-yl, 4,5-dimethyl-imidazol-2-yl, imidazolidin-1-yl-2-one, 1-methyl-imidazolidin-5-yl-2,4-dione, 1-methyl-benzimidazol-5-yl, pyridin-3-yl, oxazol-2-yl, oxazolidin-5-yl-2,4-dione, thiazolidin-5-yl-2,4-dione, isoxazol-3-yl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 5-(dimethylamino)-1,3,4-oxadiazol-2-yl, thiazol-2-yl, 5-(dimethylamino)-1,3,4-thiadiazol-2-yl and 1,3,4-triazol-2-yl;
 or a tautomer or a pharmaceutically acceptable salt thereof. 
 
     
     
       9. A compound as in  claim 4 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 8-fluoro-naphth-2-yl and 1-ethyl-4-fluoro-indazol-6-yl;
 R 1  is hydrogen; 
 R 2  is hydrogen; 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of —C(ethyl) 2 -, —C(ethyl) 2 -CH 2 —, —CH(isopropyl)-CH 2 —, -(anti)-CH(isopropyl)-CH 2 —, —C(ethyl) 2 -(E)-CH═, —C(ethyl) 2 -(Z)—CH═, —CH(isopropyl)-(E)-CH═, —CH(isopropyl)-(Z)—CH═, and —CH(isopropyl)-C(O)—NH—; wherein the X group is incorporated in the orientation as listed; 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of pyrrolidin-3-yl-2-one, S-pyrrolidin-3-yl-2-one, piperidin-1-yl-2-one, 1-(methylsulfonyl)-piperidin-4-yl, morpholin-4-yl, tetrahydropyran-4-yl, tetrahydro-thiopyran-4-yl, tetrahydro-thiopyran-4-yl-1, 1-dioxide, 1-methyl-benzimidazol-5-yl, oxazol-2-yl, oxazolidin-5-yl-2,4-dione, isoxazol-3-yl and 5-(dimethylamino)-1,3,4-thiadiazol-2-yl;
 or a tautomer or a pharmaceutically acceptable salt thereof. 
 
     
     
       10. A compound as in  claim 4 , selected from the group consisting of
 6-(1-ethyl-4-fluoro-indazol-6-yl)-3-[1-ethyl-1-(1H-tetrazol-5-yl)propyl]-1H-pyridin-2-one, Compound #3; 
 6-(1-ethyl-4-fluoro-indazol-6-yl)-3-[1-ethyl-1-(4H-1,2,4-triazol-3-yl)propyl]-1H-pyridin-2-one, Compound #5; 
 (5E)-5-[2-ethyl-2-[6-(8-fluoro-2-naphthyl)-2-oxo-1H-pyridin-3-yl]butylidene]oxazolidine-2,4-dione, Compound #6; 
 6-(1-ethyl-4-fluoro-indazol-6-yl)-3-[1-ethyl-1-[(E)-(2-oxopyrrolidin-3-ylidene)methyl]propyl]-1H-pyridin-2-one, Compound #16; 
 6-(1-ethyl-4-fluoro-indazol-6-yl)-3-[1-ethyl-1-(5-methyl-4H-1,2,4-triazol-3-yl)propyl]-1H-pyridin-2-one, Compound #21; 
 6-(1-ethyl-4-fluoro-indazol-6-yl)-3-(1-ethyl-1-oxazol-2-yl-propyl)-1H-pyridin-2-one, Compound #30; 
 6-(1-ethyl-4-fluoro-indazol-6-yl)-3-[1-ethyl-1-(1H-imidazol-2-yl)propyl]-1H-pyridin-2-one, Compound #31; 
 (5Z)-5-[2-ethyl-2-[6-(1-ethyl-4-fluoro-indazol-6-yl)-2-oxo-1H-pyridin-3-yl]butylidene]oxazolidine-2,4-dione, Compound #55; 
 (5Z)-5-[2-[6-(8-fluoro-2-naphthyl)-2-oxo-1H-pyridin-3-yl]-3-methyl-butylidene]oxazolidine-2,4-dione, Compound #62; 
 (5Z)-5-[2-[6-(8-fluoro-2-naphthyl)-5-methyl-2-oxo-1H-pyridin-3-yl]-3-methyl-butylidene]oxazolidine-2,4-dione, Compound #75; 
 and tautomers and pharmaceutically acceptable salts thereof.